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School of Pharmacy and Pharmaceutical Sciences

Dr Aleksandra Galetin PhD

Photograph of Aleksandra Galetin

Senior Lecturer of Drug Metabolism and Pharmacokinetics

University of Manchester
School of Pharmacy and Pharmaceutical Sciences
Room 3.036
Stopford Building
Oxford Road
Manchester
M13 9PT

 

Memberships of Committees and Professional Bodies

  • Member of Management Committee of the Centre for Applied Pharmacokinetic Research
  • Member of the ISSX Scientific Affairs Committee representing the European region
  • Associated Editor of Current Drug Metabolism
  • Person Designated for the Human Tissue for the School of Pharmacy and member of the Biological Safety Committee
  • Member of the School of Pharmacy and Pharmaceutical Sciences Teaching Standards Committee

Research

Physiologically-based approach to the prediction of hepatic uptake transporter (OATP1B1) drug-drug interactions

Role of uptake transporters in the assessment of drug clearance

Prediction of Intestinal first-pass metabolism

Extrapolation of in vitro drug clearance by glucuronidation and sulphation to in vivo

In vitro approaches to mechanism-based inhibition and induction drug-drug Interactions

 

Methodological Knowledge

Role of uptake transporters in the assessment of drug clearance

The interplay between hepatic uptake transporters and metabolic enzymes is investigated using a range of in vitro cellular systems. Uptake kinetics of a wide range of therapeutically used drugs with combined uptake transporter-metabolism disposition is explored. Mechanistic modelling of in vitro data is performed, accounting for uptake, bidirectional passive diffusion, intracellular binding and metabolism. The contribution of single/multiple transporters and interplay with metabolic enzymes to the overall drug clearance will be assessed using the in house PBPK models.

Prediction of Intestinal First-Pass Metabolism

For certain orally administered drugs the interplay between the efflux transporters and metabolic enzymes in the enterocytes is indicated as a contributing factor to the low intestinal availability. Current research project is assessing the utility of human intestinal microsomes and different transporter cell lines for the prediction of intestinal first-pass metabolism and associated inter-individual variability. Predictive utility of minimal physiologically-based QGut model and more complex physiologically-based pharmacokinetic modelling approaches are assessed.

Extrapolation of in vitro drug clearance by glucuronidation and sulphation to in vivo

In vitro-in vivo prediction and application of in silico methods for clearance prediction of conjugation metabolism (glucuronidation and sulphation) has proved challenging and less definitive than for cytochrome P450s. Apart from liver, conjugative enzymes are also localized extrahepatically (intestine and kidney) and may contribute significantly to the overall elimination and drug-drug interactions. Therefore, assessment of metabolic stability of a range of selected drugs/exogenous xenobiotics is performed using microsomal and cytosolic in vitro systems prepared from extrahepatic tissues. Appropriate scaling strategies are explored to achieve in vivo prediction. In vitro data generated complement physiologically-based pharmacokinetic modelling activioties and allow mechanistic integration of the contribution of extrahepatic tissues to the drug elimination.

In vitro Approaches to Mechanism-based Drug-drug Interactions

Drug-drug interaction (DDI) area of research involves a number of PhD projects investigating a wide range of related topics. General prediction strategy is extended to induction intreactions, contribution of multiple inhibitors (or metabolites) and/or the consequence of multiple inhibition mechanisms to DDIs. Investigation of the impact of the hepatic uptake transporters, in particular OATP1B1, and prediction of related DDIs are assessed using PBPK modelling and  in vitro data generated in transporter expression systems and hepatocytes.  Change of inhibitor concentration with time and impact of population variability are assessed using either the in house PBPK models or Simcyp population-based simulator.

 

Teaching

Under-graduate teaching:

PHAR10300  The Patient

PHAR10200 The Pharmacist

PHAR20511  Drug Toxicity

PHAR30312  Drug Metabolism and Disposition

PHAR40281  Pharmacokinetics - Dosage Regimen Design

 

Postgraduate teaching:

MSc in Modelling and Simulation in Pharmacokinetics & Pharmacodynamics, University of Manchester

 

Biography

Dr Aleksandra Galetin is a Senior Lecturer in Drug Metabolism and Pharmacokinetics. In November 2004 she was appointed as Pfizer Lecturer in The School of Pharmacy, following her position as a Postdoctoral Research Associate in the Centre for Applied Pharmacokinetic Research, University of Manchester. The incorporation of atypical homo/heterotropic cooperativity phenomena associated with CYP3A4 (and other enzymes) into the in vitro-in vivo prediction of either clearance or drug-drug interactions is her substantial contribution to these research areas.

She has published 4 book chapters, 42 publications in leading peer reviewed journals and a number of presentations at international conferences. Current research activities focus on the mechanistic integration of in vitro data using physiologically-based pharmacokinetic modelling for the assessment of hepatic uptake transporters and their contribution to drug-drug interactions. Additional research activities include assessment of the contribution of P450 and conjugation metabolism to intestinal first-pass and implication on in vitro-in vivo extrapolation of drug clearance. Dr Galetin is on the Management Board of the Centre for Applied Pharmacokinetic Research where research is carried out, supported by collaborations with different pharmaceutical companies, academic groups both in UK and worldwide (see Selected Publications) and government funding. She is currently supervising 9 PhD students, 5 as a principal investigator.
 

 

Qualifications

  • 2001 – PhD, School of Pharmacy and Pharmaceutical Sciences, University of Manchester
  • 1998 – MSc, School of Pharmacy, University of Belgrade
  • 1993 – School of Pharmacy, University of Belgrade
 

Collaborators and affiliated staff

  • Current PhD Students: K Menochet, S Tate, C Lager, K Gill, O Hatley, A Ufuk, R Sullivan, N Tsamandouras and D Scotcher
  • Postdoctoral Research Associate: M Gertz
  • Former members of the group (PhD and Postdoctoral Research Associates): J Henshall, H Burt, L Hinton, P Kilford, H Cubitt, E Guest, H Graham, I Templeton and Y Yabe

 

 

Selected publications

2012

  • 4. Jones HM, Barton HA, Lai Y, Bi Y, Kimoto E, Kempshall S, Tate SC, El-Kattan A, Houston JB, Galetin A and Fenner KS. (2012). Mechanistic pharmacokinetic modelling for the prediction of transporter-mediated disposition in human from sandwich culture human hepatocyte data. Drug Metab Dispos, 40(5), 1007-1017. eScholarID:159145
  • Gill KL, Houston JB, Galetin A. (2012). Characterization of In Vitro Glucuronidation Clearance of a Range of Drugs in Human Kidney Microsomes: Comparison to Liver and Intestinal Glucuronidation and Impact of Albumin. Drug Metab Dispos, 40(4), 825-835. eScholarID:159144
  • Graham H, Walker M, Jones O, Galetin A and Aarons L. (2012). Comparison of in vivo and in silico methods used for prediction of tissue:plasma partition coefficients in rat. J Pharm Pharmacol, 64(3), 383-396. eScholarID:159143
  • Ménochet K, Kenworthy KE, Houston JB and Galetin A. (2012). Simultaneous Assessment of Uptake and Metabolism in Rat Hepatocytes: A Comprehensive Mechanistic Model. J Pharmacol Exp Ther, 341(1), 2-15. eScholarID:159142

2011

  • Hatley O, Jones C, Galetin A and Rostami-Hodjegan, A. (2011). Methodology Optimisation in Intestinal Microsome Preparation: Implications for Scaling Approaches?. Presented at AAPS Meeting, Washington. eScholarID:147596
  • Hatley O, Jones C, Galetin A and Rostami-Hodjegan. (2011). Methodology Optimisation in Intestinal Microsome Preparation: Implications for Scaling Approaches?. Presented at 17th North American Regional ISSX Meeting. eScholarID:147586
  • Cubitt HE, Houston JB, Galetin A. (2011). Prediction of human drug clearance by multiple metabolic pathways: integration of hepatic and intestinal microsomal and cytosolic data. Drug Metab Dispos, 39(5), 864-73. eScholarID:132503 | DOI:10.1124/dmd.110.036566
  • Gertz M, Houston JB, Galetin A. (2011). Physiologically based pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A substrates with high intestinal extraction. Drug Metab Dispos, 39(9), 1633-1642. eScholarID:132526 | DOI:10.1124/dmd.111.039248
  • Guest EJ, Aarons L, Houston JB, Rostami-Hodjegan A, Galetin A. (2011). Critique of the two-fold measure of prediction success for ratios:application for the assessment of drug-drug interactions. Drug Metab Dispos, 39(2), 170-173. eScholarID:95952 | DOI:10.1124/dmd.110.036103
  • Guest EJ, Rowland-Yeo K, Rostami-Hodjegan A, Tucker GT, Houston JB, Galetin A. (2011). Assessment of Algorithms for Predicting Drug-Drug Interactions via Inhibition Mechanisms: Comparison of Dynamic and Static Models. Br J Clin Pharmacol, 71(1), 72-87. eScholarID:95959 | DOI:10.1111/j.1365-2125.2010.03799.x
  • Menochet K, Kenworthy KE, Houston JB, Galetin A. (2011). Simultaneous Assessment of Uptake and Metabolism in Rat Hepatocytes: A Comprehensive Mechanistic Model. doi:10.1124/jpet.111.187112. J Pharmacol Exp Ther, eScholarID:147627
  • Templeton IE, Houston JB, Galetin A. (2011). Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells. Drug Metab Dispos, 39(10), 1921-1929. eScholarID:132529 | DOI:10.1124/dmd.111.040824
  • Yabe Y, Galetin A, Houston JB. (2011). Kinetic characterization of rat hepatic uptake of 16 actively transported drugs. Drug Metab Dispos, 39(10), 1808-1814. eScholarID:132532 | DOI:10.1124/dmd.111.040477

2010

  • Houston JB and Galetin A. (2010). In vitro techniques to study drug-drug interactions of drug metabolism: Cytochrome P450. In Pang KS, Rodrigues AD, Peter RM (Ed.), Enzymatic and Transporter Based Drug-Drug Interactions: Progress and Future Challenges. (pp. 169-215). USA: Springer. eScholarID:79991
  • Galetin A, Gertz M and Houston JB. (2010). Contribution of intestinal cytochrome P450-mediated metabolism to drug-drug inhibition and induction interactions. Drug Metab Pharmacokinet, 25(1), 28-47. eScholarID:79988 | DOI:10.2133/dmpk.25.28
  • Gertz M, Harrison A, Houston JB, Galetin A. (2010). Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug Metab Dispos, 38(7), 1147-1158. eScholarID:79990 | DOI:10.1124/dmd.110.032649

2009

  • HE Cubitt, Houston JB, Galetin A. (2009). Relative Importance of Intestinal and Hepatic Glucuronidation-Impact on the Prediction of Drug Clearance. Pharm Res, 26, 1073-1083. eScholarID:1d18777 | DOI:10.1007/s11095-008-9823-9
  • PJ Kilford, R Stringer, B Sohal, Houston B, Galetin A. (2009). Prediction of Drug Clearance by Glucuronidation from in Vitro Data: Use of Combined Cytochrome P450 and UDP-Glucuronosyltransferase Cofactors in Alamethicin-Activated Human Liver Microsomes. Drug Metab Dispos, 37, 82-89. eScholarID:1d18776 | DOI:10.1124/dmd.108.023853

2008

  • Galetin A, Michael Gertz, Houston B. (2008). Potential role of intestinal first-pass metabolism in the prediction of drug-drug interactions. Expert Opinion Drug Metab Toxicol, 4, 909-22. eScholarID:1d17787 | DOI:10.1517/17425255.4.7.909
  • Houston B, Galetin A. (2008). Methods for Predicting In Vivo Pharmacokinetics Using Data from In Vitro Assays. Curr Drug Metab, 9(9), 940-51. eScholarID:1d18774
  • Laura Hinton, Galetin A, Houston JB. (2008). Multiple inhibition mechanisms and prediction of Drug-Drug Interactions: Status of Metabolism and Transporter Models as Exemplified by Gemfibrozil-Drug Interactions. Pharmaceutical Research, eScholarID:1d16778 | DOI:10.1007/s11095-007-9446-6
  • Michael Gertz, John D Davis, Anthony Harrison, Houston B, Galetin A. (2008). Grapefruit juice-drug interaction studies as a method to assess the extent of intestinal availability: utility and limitations. Curr Drug Metab, 9, 785-795. eScholarID:1d18096 | DOI:10.2174/138920008786049276
  • Michael Gertz, Peter J Kilford, Houston B, Galetin A. (2008). Drug lipophilicity and microsomal protein concentration as determinants in the prediction of the fraction unbound in microsomal incubations. Drug Metabolism and Disposition, 36, 535-542. eScholarID:1d17054 | DOI:10.1124/dmd.107.018713

2007

  • Galetin A, Laura Hinton, Howard Burt, Houston B. (2007). Maximal inhibition of intestinal first-pass metabolism as a pragmatic indicator of intestinal contribution to the drug-drug interactions for CYP3A4 cleared drugs. Current Drug Metabolism, 8, 685-693. eScholarID:1d16777

2006

  • Brown H, Galetin A, Hallifax D, Houston J B. (2006). Prediction of in vivo drug-drug interactions from in vitro data: prototypic drug-drug interactions involving CYP2C9, CYP2D6 and CYP3A4. Clinical Pharmacokinetics, 45, 1035-1050. eScholarID:1d14359
  • Galetin A, Burt H, Gibbons L, Houston J.B. (2006). Prediction of time-dependent CYP3A4 drug-drug interactions: impact of enzyme degradation, parallel elimination pathways, and intestinal inhibition. Drug Metabolism Disposition, 34, 166-175. eScholarID:1d12869 | DOI:10.1124/dmd.105.006874
  • Galetin A, Houston B. (2006). Intestinal and hepatic metabolic activity of five cytochrome P450 enzymes: Impact on prediction of first-pass metabolism. The Journal of Pharmacology and Experimental Therapeutics, 318, 1220-1229. eScholarID:1d13656

2005

  • Brown H, Kiyomi Ito, Galetin A, Houston B. (2005). Prediction of in vivo drug-drug interactions from in vitro data: impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant. Br J Clin Pharm, 60(5), eScholarID:1d11360
  • Galetin A, Kiyomi Ito, Hallifax D, Houston J.B. (2005). CYP3A4 Substrate selection and substitution in the prediction of potential drug-drug interactions. Journal of Pharmacology and Experimental Therapeutics, 314, 180-190. eScholarID:1d11047 | DOI:10.1124/jpet.104.082826
  • Houston B, Galetin A. (2005). Modelling atypical CYP3A4 kinetics: principles and pragmatism. Archives Biochem Biophys, 433, 351-360. eScholarID:1d9619

2004

  • Uchaipichat V, Mackenzie P.I, Guo X-H, Gardner-Stephen D, Galetin A, Houston J.B, Miners J.O. (2004). Human UDP-Glucuronosyltransferases: Isoform selectivity and kinetics of 4-methylumbelliferone and 1-naphthol glucuronidation, effects of organic solvents, and inhibition by diclofenac and probenecid. Drug Metab. Dispos, 32, 413-423. eScholarID:1d25774 | DOI:10.1124/dmd.104.000844

2003

  • Galetin A, ClarkeS.E, Houston J.B. (2003). Multisite kinetic analysis of interactions between prototypical CYP3A4 subgroup substrates: midazolam, testosterone and nifedipine. Drug Metab.Dispos, 31, 1108 - 1116. eScholarID:1d6971 | DOI:10.1124/dmd.31.9.1108

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